Project Summary/Abstract Prolonged consumption of a high saturated fat (SF) diet is known to cause brain inflammation, and has recently been shown to impair dopamine neurotransmission similar to chronic drug use. Brain imaging studies show that obesity gradually reduces dopamine neurotransmission, but mechanisms that drive these changes are not known. A hallmark of SF-induced obesity is insulin resistance and chronic inflammation that impacts both the brain and peripheral tissues. Insulin signaling is essential to fine tune dopamine neurotransmission and helps trigger satiety circuits, but insulin signaling is weakened by pro-inflammatory cytokines. Cytokines are released in the brain by immune cells called microglia and astrocytes, which can be directly triggered by SF. This project seeks to identify whether these glial immune cells respond to SF in a way that increases inflammatory cytokines, and whether the increase in cytokines alters dopamine neurotransmission alone or by interfering with insulin signaling. Determining the role of glial cells in this process would provide a therapeutic target to normalize dopamine neurotransmission in obesity, and restore normal satiety signals. We will also explore the effectiveness of anti-inflammatory unsaturated fatty acids to reduce brain inflammation and restore dopamine neurotransmission. We hypothesize that a diet enriched with flaxseed oil, a potent source of anti-inflammatory omega 3 fatty acids, will attenuate the actions of pro-inflammatory cytokines (TNF-?, IL-6, and IL-1?) induced by the SF diet, improve insulin sensitivity, and restore deficits in dopamine neurotransmission after prolonged SF intake. We will also test whether inflammation caused by saturated fat-induced obesity interferes with insulin- induced satiety. Data collected from this project will demonstrate the efficacy of flaxseed oil to treat obesity- related changes in dopamine neurotransmission, and will provide a novel treatment approach to prevent over- eating. Ultimately, identifying the impact of inflammation of dopamine neurotransmission, and characterizing how these changes in dopamine signaling interfere with satiety will help us understand how diet-induced obesity leads to dysregulated food intake, promoting over-eating when physiological needs have been met.